| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute manic episodes associated with Bipolar I Disorder |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10004939 |
| E.1.2 | Term | Bipolar I disorder |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Study Primary Objective:
• To evaluate the efficacy of iloperidone monotherapy compared to placebo in the treatment of adult patients with bipolar I disorder experiencing an acute manic or mixed episode as measured by reduction in the Young Mania Rating Scale (YMRS) total score at Week 4
Primary Objective for the Optional Long-Term Open-Label Phase:
• To explore the long-term safety and tolerability of dosing with iloperidone over an additional 52 weeks of treatment
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| E.2.2 | Secondary objectives of the trial |
•Evaluate efficacy of iloperidone monotherapy vs placebo in the treatment of adult patients diagnosed with bipolar I disorder experiencing an acute manic or mixed episode as measured by:
1) improvements in the CGI-S
2) reduction in the YMRS total score at each trial visit
3) improvement in clinical symptoms in the CGI-C
4) improvement in clinical symptoms in the MADRS
•Assess the rate of YMRS responders. A YMRS responder is defined as at least a 50% decrease from baseline in YMRS total score
•Assess safety & tolerability of iloperidone vs placebo in the treatment of adult patients in an acute manic or mixed episode of bipolar I disorder as measured by changes in vital signs and weight, laboratory analytes, ECGs, and the incidence and severity of TEAEs and extrapyramidal symptoms using the BARS, SAS, and the AIMS
Exploratory objective: conduct a whole genome association scan to identify potential markers of response and safety for a bipolar indication |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet the following criteria for inclusion in the study:
1. Patients must provide written informed consent (IC) before any assessment is performed. Additionally, if a patient is not mentally stable to provide consent their legal guardian must also sign the inform consent form in accordance with the regulatory requirements for their respective country.
2. Males or non-fecund females (i.e., surgically sterilized, if procedure was done 6 months before screening or patient is postmenopausal, without menses for 12 months before screening), or females of childbearing potential using adequate contraception from 1 month prior to randomization through 1 month after the last dose of study medication.
Note: Examples of acceptable methods of contraception for females include the use of 2 independent barrier methods, hormonal contraception plus 1 barrier method, or surgically sterilized partner.
3. Patients must be 18 through 65 years of age inclusive.
4. Patients with Body Mass Index (BMI) of >18 and < 40 kg/m2 (BMI = weight (kg)/ [height (m)]2).
5. Patients must be cooperative, able to ingest oral medication, willing to take iloperidone or placebo, and willing to complete all aspects of the study, including hospitalizations.
6. Patients must meet the Diagnostic and Statistical Manual of Mental Disorder, Fifth Edition (DSM-5) diagnosis of bipolar I disorder, manic or mixed type, as confirmed by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (SCID) manic or mixed type with or without psychotic symptoms and have had the diagnosis for at least one year.
7. Patients must have had at least one prior documented manic or mixed episode (with or without psychotic symptoms) that required treatment prior to screening.
8. Patients must have a Clinical Global Impressions of Severity (CGI-S) – Severity of Illness (Mania) score of at least 4 at baseline.
9. Patients must have a Young Mania Rating Scale (YMRS) total score ≥20 at screening and baseline.
10. Patients must have ≥ 4 on at least 2 of 4 YMRS items (irritability, speech, content, disruptive/aggressive behavior).
11. Patients must have a Montgomery-Asberg Depression Rating Scale (MADRS) total score < 18.
12. Patients must be voluntarily hospitalized for current manic episode.
13. Patients must have no medical contraindication for oral treatment with iloperidone as confirmed by medical history, physical examination, electrocardiogram (ECG), and clinical laboratory tests, which are all within the normal range, or, if abnormal, judged not to be clinically significant by the principal Investigator.
A patient is eligible for enrollment into the Long-Term Open-Label Phase of this study if he/she meets the following criteria:
• Completes the Short-Term Double-Blind Phase through Day 28.
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| E.4 | Principal exclusion criteria |
1 Patients with a DSM-5 diagnosis of a psychiatric disorder other than bipolar I disorder that was the primary focus of treatment within the previous 6 m.
2 Patients with diagnosis or history suggestive of chemical dependence according to DSM-5 criteria, or toxic psychosis in the preceding 6 m., or a clinical presentation possibly confounded by the use of recreational drugs or alcohol
3 Patients experiencing a first manic episode or meeting criteria for
rapid cycling
4 Patients who are mentally disabled (moderate to severe) and cannot understand the IC or participate fully in the assessments.
5 Patients with a significant brain trauma or a coma lasting more than 24 h.
6 Patients who are currently at imminent risk of harm to self or others
7 Patients with a positive urine drug screen (at the screening visit) for amphetamines, cocaine, PCP, benzodiazepines, or barbiturates will be excluded. If opiates are positive at screening, patients must provide sufficient evidence that they have been prescribed these medications and are taking them as prescribed. Patients must also be clinically evaluated for dependency and excluded if there is sufficient suspicion. If benzodiazepine is positive at screening, patients may be allowed to continue if the use is PRN. If benzodiazepine use is chronic, patients will still need to be excluded
8 Patients known to suffer from blindness, deafness, language
difficulties, or any other sensory or motor deficits that may prevent the patient from completing any of the study requirements
9 Patients who have suffered from significant physical illness in the 4w period preceding baseline will be excluded, unless the Investigator provides a rationale for including a specific patient and has approval of the Medical Monitor
10 Patients who suffer from other clinically significant medical
conditions which could be expected to progress, recur, or change to such an extent that they may put the patient at special risk or bias the assessment of the clinical and the mental status of the patient to a significant degree will be excluded. This includes any nonpsychiatric coexistent disease state that has not been maintained in a stable condition for at least 3 m prior to baseline
11 Patient with known congenital long QT syndrome, Brugada syndrome, or other cardiac abnormality that would increase the risk of ventricular arrhythmia
12 Patients who suffer from any clinically significant disease of the
gastrointestinal system, liver, or kidneys, or any abnormal condition that compromises the function of these systems and could result in the possibility of altered absorption, excess accumulation, or impairment of metabolism or excretion of the study medication
13 Patients that have a clinically significant abnormal laboratory finding, which remained abnormal upon being repeated ONCE and that suggests a medical condition that would put the patient at special risk or significantly bias assessment of the patient's clinical status
14 Patients that have one or more of the following serological results:
a Current hepatitis C infection
b A positive hepatitis B surface antigen (HbsAg)
c Elevated (> or = 1.5 times the upper lime of normal) LFTs (SGOT,
SGPT, LDH, alkaline phosphate, or bilirubin) and one of the following:
positive hepatitis A (HAV IgM) or positive hepatitis B core antibody
(HBcAb-IgM)
15 Patients with a current diagnosis or past history of epilepsy, major
head trauma, or progressive neurological disease (other than tardive
dyskinesia or drug-induced extrapyramidal side effects)
16 Patients with history of priapism that required treatment with
surgical interventions
17 Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive β human chorionic gonadotropin laboratory test (>5 mIU/mL)
18. Patients with known hypersensitivity to drugs chemically related to benzisoxazoles
19 Patients treated with a long-acting injectable antipsychotic within
one treatment cycle of screening
20 Patients who receive, during the 30 d immediately prior to screening, any experimental drug not approved for marketing in the country
21 Patients who received, during the 30 days preceding baseline, any
drug known to cause major organ system toxicity
22 Patients who received electroshock therapy in the 3 m preceding
baseline
23 Patients who likely require continuous treatment with any other
psychotropic drug, including antidepressants or mood stabilizers, during the double-blind short-term treatment phase
24 Patients who have experienced neuroleptic malignant syndrome
25 Patients with history of treatment with clozapine, unless approved by Medical Monitor
26 Patients whose psychotic symptoms have failed to improve following sufficient exposure to 2 antipsychotic treatments, over the last 2 y
27 Patients randomized to iloperidone within the last 4 y |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy outcome measure is the change from baseline in the Young Mania Rating Scale (YMRS) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| YMRS total score at Week 4. |
|
| E.5.2 | Secondary end point(s) |
Mean baseline-to-endpoint change in total score using following parameters:
Efficacy parameters:
• Young Mania Rating Scale (YMRS)
• Overall and mania severity of illness for Clinical Global Impression of Severity (CGI-S)
• Clinical Global Impression of Change (CGI-C)
• Montgomery-Asberg Depression Rating Scale (MADRS)
Safety parameters:
• Adverse Events (AEs) and proportion of patients withdrawing due to AEs
• EPS scale scores as measured by Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), and Barnes Akathisia Rating Scale (BARS)
• Metabolic risk factors, clinical chemistry, hematology, vital signs, and weight
• Columbia Suicide-Severity Rating Scale (C-SSRS)
• CYP2D6 genotyping
• 12-lead electrocardiograms (ECG)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy parameters:
• YMRS is completed at visits 1 to 8, 11, 14, 15 and 16
• CGI-C is completed at visits 3 to 8, 11, 14, 15 and 16
• CGI-S is completed at visits 2 to 8, 11, 14, 15 and 16
• MADRS is completed at visits 2, 3, 5, 6, 7, 8, 11, 14, 15 and 16
Safety parameters:
• SAS, BARS and AIMS are completed at visits 1 to 8, 11, 14, 15 and 16
• C-SSRS is completed in all visits
• CYP2D6 genotyping is performed at screening (visit 1)
Safety will be monitored throughout the entire study and as described in study protocol.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| There are 2 phases: A short term double-blind treatment followed by an Optional Open-Label Extension |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Poland |
| Bulgaria |
| Russian Federation |
| Ukraine |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last subject |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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